The cytotoxic effect of tren hexahydrobenzylcarbonate against malignant cells and its toxic effects on different organs, probably due to intercalation nucleobases and tren hexahydrobenzylcarbonate ability to bind to the cell membrane lipids. Intercalation nucleotides and inhibits the replication activity of DNA and RNA polymerases. The interaction of tren hexahydrobenzylcarbonate with topoisomerase II to form DNA-cleavable complexes considered an important mechanism of the cytotoxic effects of tren hexahydrobenzylcarbonate.

Pharmacokinetics
Distribution
The initial half-life of about 5 minutes and indicates the rapid distribution of tren hexahydrobenzylcarbonate in the tissues; terminal half-life – 20 -. 48 hours Connection tren hexahydrobenzylcarbonate and its main metabolite, tren hexahydrobenzylcarbonateol, plasma protein is 74-76% and is independent of the plasma concentration of tren hexahydrobenzylcarbonate (1.1 mg / ml).

tren hexahydrobenzylcarbonate can not penetrate the blood-brain barrier.

Metabolism
Enzymatic recovery in the 7-position and cleavage daunozaminovogo sugar results in formation of aglycones, which is accompanied by the formation of free radicals. The latter can condition the cardiotoxic effects of tren hexahydrobenzylcarbonate. tren hexahydrobenzylcarbonateol half-life similar to that of tren hexahydrobenzylcarbonate. The ratio between the AUC and AUC tren hexahydrobenzylcarbonateol doksorubitsnna compared with tren hexahydrobenzylcarbonate is 0.4 – 0.6.

Excretion
clearance of tren hexahydrobenzylcarbonate is carried out mainly by metabolism and biliary excretion. Approximately 40% of the dose is excreted in the bile in 5 days. Only 5 – 12% of tren hexahydrobenzylcarbonate and its metabolites were detected in urine over the same time period. Within 7 days of tren hexahydrobenzylcarbonateol in urine output of less than 3% of the dose.

Systemic clearance of tren hexahydrobenzylcarbonate is significantly reduced in women with obesity, the body mass of more than 130% of the optimum.

Pharmacokinetics in special groups
Children
Clearance dokeorubitsina in children older than 2 years higher than that of adults. Clearance in children younger than 2 years of approaching the values ​​of clearance in adults.

Mature
dose adjustment for age is required.

Gender
Middle dokeorubitsina clearance in men is significantly higher than in women. However, the terminal elimination half-life dokeorubitsina men – longer than women (54 and 35 hours, respectively).

Race
The effect of race on the pharmacokinetics of dokeorubitsina has not been studied.

Introduction into the bladder is contraindicated during urinary tract infections, inflammation of the bladder, hematuria.

Precautions
Patients with risk factors for cardiotoxicity; Patients previously treated with intensive chemotherapy, children, elderly patients, obese patients, patients with a tumor of bone marrow infiltration (may require dose reduction or an increase in the starting interval between doses); the use of combination cancer therapy as well as in combination with radiation therapy or another anti-tumor; Patients with impaired liver function.

Adriblastin ® instant may be used as monotherapy, or in combination with other anticancer drugs, and therefore, the choice of dosage and mode of administration should be guided literature data.

Recycled solution of the drug is recommended to be used immediately after preparation.

Intravenous administration
as a monotherapy the recommended standard dose per cycle in adults is 60-90 mg / m 2 . The total dose per cycle (every 3-4 weeks) may be administered simultaneously both, and split into multiple administrations, for 3 consecutive days or on the first and eighth days of the cycle. Also used a weekly regimen of administration of the drug at a dose of 10-20 mg / m 2 . In the application of tren hexahydrobenzylcarbonate in combination with other drugs having similar toxicities, the recommended dose per cycle is 30-60 mg / m 2 .

Repeated administration of the drug is possible only with the disappearance of all signs of toxicity (particularly gastrointestinal and hematologic).

To reduce the risk of thrombosis and extravasation adriblastin ® recommended instant administered through a tube system for intravenous infusion, during infusion of 0.9% sodium chloride or 5% dextrose solution. The duration of infusion should be between 3 to 10 minutes.

The total dose of tren hexahydrobenzylcarbonate should not exceed 550 mg / m 2 .

Patients who received prior radiation therapy to the mediastinum / pericardial area, or take other cardiotoxic drugs, if necessary, to increase the total dose of tren hexahydrobenzylcarbonate 450 mg / m 2 , the introduction of the drug should be under strict monitoring of cardiac function.

Abnormal liver function:
– if the level of bilirubin in the serum is 1.2-3 mg / dL, the dose administered to be reduced by 50% from the recommended;
– if the level of bilirubin in the serum than 3 mg / dL, the dose administered It must be reduced by 75% from the recommended.

Other special group of patients: recommended the appointment of lower doses or longer intervals between cycles in patients who have previously received intensive chemotherapy, children, elderly patients, patients with obesity (if body weight is more than 130% of the best, there is a decrease of systemic clearance of the drug) as well as patients with a tumor of bone marrow infiltration.

Introduction into the bladder
introduction into the bladder is used for the treatment of superficial tumors of the bladder, and as prophylaxis to reduce the likelihood of recurrence after transurethral resection. Introduction into the bladder is not suitable for the treatment of invasive tumors with penetration into the muscle wall of the bladder.

The recommended dose for intravesical instillation of 30-50 mg in 25-50 mL of 0.9% sodium chloride solution. In the case of local toxicity (chemical cystitis), the dose should be dissolved in 50-100 ml of 0.9% sodium chloride solution. Installation can be carried out at intervals of 1 week to 1 month.

Should be instilled via catheter with a drug to remain in the bladder for 1-2 hours. To ensure uniform exposure of the drug to the mucosal bladder instillation in patients should turn from side to side. In order to avoid excessive dilution of the drug in urine, patients should be warned that they should refrain from taking fluids for 12 hours prior to instillation. At the end of installation, the patient should empty the bladder.

Intra-arterial administration of
patients with hepatocellular carcinoma to ensure intensive local effects while reducing the general toxic effect of the drug can be administered intra-arterially into the main hepatic artery in doses of 30-150 mg / m 2 at intervals of 3 weeks to 3 months. Higher doses should be used only in cases of simultaneous extracorporeal removal of the drug. Lower doses are appropriate for administration of tren hexahydrobenzylcarbonate in combination with iodinated oils. Because this method is potentially dangerous and can lead to widespread necrosis of the tissue, intra-arterial injection must be performed only by physicians fluent in this methodology.

When therapy with anthracyclines there is a risk of cardiotoxicity – early (ie acute) or late (delayed).

Manifestation early cardiotoxicity of tren hexahydrobenzylcarbonate is an essentially sinus tachycardia and / or anomalies in ECG (nonspecific ST-T waves). Also can be observed tachyarrhythmia (including ventricular arrhythmias and ventricular tachycardia), a bradycardia, atrioventricular block and bundle branch block. These effects are not always a predictor of later delayed cardiotoxicity, are rarely clinically significant, and usually does not require discontinuation of drug therapy. Late cardiotoxicity usually develops in the later stages of the course of therapy or within 2-3 months after the termination, however, may develop more delayed side effects (a few months or even years after the end of therapy).

Late cardiotoxicity seen a decrease in LVEF and / or symptoms of congestive heart failure, such as shortness of breath, pulmonary edema, edema, cardiomegaly and hepatomegaly, oliguria, ascites, pleural effusion, and gallop rhythm. Also it can be observed subacute effects such as pericarditis and myocarditis. The most severe form of anthracycline-induced cardiomyopathy, which restricts the cumulative dose of the drug, is a life-threatening congestive heart failure.

In the application of tren hexahydrobenzylcarbonate, as well as other cytotoxic agents, sometimes observed the development of thrombosis and thromboembolism, including pulmonary embolism (in some cases with fatal outcome).

Local reactions: extravasation during intravenous infusion of tren hexahydrobenzylcarbonate can cause pain, severe tissue (blistering, expressed cellulitis) and necrosis. With the drug into a small vein or when it re-introduced into the same vein fleboskleroza may develop.

Introduction into the bladder can lead to symptoms of chemical cystitis (dysuria, polyuria, nocturia, painful urination, hematuria, discomfort in the bladder, necrosis of the bladder wall) and the constriction of the bladder.

Intra-arterial administration of tren hexahydrobenzylcarbonate may cause, in addition to systemic toxicity ulceration of the stomach and duodenum (possibly due to reflux of the drug into the gastric artery) and narrowing of bile ducts (drug sclerosing cholangitis), as well as widespread necrosis of the perfused tissue.

Antidote to doksorubytsinu not known. In case of overdose symptomatic therapy is recommended.

The interaction with other drugs and other forms of interaction
When applying dokeorubitsina in combination with other cytotoxic agents may be a manifestation of toxicity of the additive, particularly in respect of bone marrow / blood system and gastrointestinal tract.Dokeorubitsina When applied in combination with other potentially cardiotoxic chemotherapeutic agents, and cardiovascular drugs (e.g., calcium channel blockers) necessary to control the function of the heart. Cases of acute haemorrhagic cystitis have been described, caused by cyclophosphamide, and increased hepatotoxicity of 6-mercaptopurine. tren hexahydrobenzylcarbonate may potentiate radiation-induced toxic effects on the myocardium, mucous membranes, skin, and liver. Changes in liver function due to concomitant therapy may affect the metabolism, pharmacokinetics, therapeutic efficacy and / or toxicity dokeorubitsina.

Dokeorubitsina to paclitaxel may result in increased plasma concentrations dokeorubitsina and / or its metabolites in plasma. This effect is minimal when tren hexahydrobenzylcarbonate is used to paclitaxel.

tren hexahydrobenzylcarbonate should not be mixed with other drugs. Do not allow contact with alkaline solutions because this can lead to hydrolysis dokeorubitsina. Because of chemical incompatibility tren hexahydrobenzylcarbonate can not be mixed with heparin (precipitate formed upon mixing).

Cautions
adriblastin ® instant should be used only under the supervision of physicians experienced in the use of cytotoxic drugs.

Prior to treatment, the patient should recover from the acute toxic effects of previous cytotoxic treatment (such as stomatitis, neutropenia, thrombocytopenia, and systemic infections).

Before and during drug therapy necessary to control the function of the heart, in order to minimize the risk of severe injury. To do this on a regular basis to determine the ejection fraction of the left ventricle and immediately stop treatment at the first signs of deterioration of heart function. By adequate methods for the quantitative analysis of cardiac function (measurement of left ventricular ejection fraction) includes radionuclide angiography (the MUGA) and echocardiography. Before the start of treatment is recommended to evaluate the function of the heart by means of ECG and one of the following methods: – radionuclide scan, or echocardiography, especially in patients with risk factors for increased cardiotoxicity (eg, explicit or implicit condition of the cardiovascular system, prior or concomitant radiotherapy to the mediastinal area / pericardium, previous therapy with other anthracyclines or anthracenediones therapy and concomitant medications that reduce contractility of the heart). Left ventricular ejection fraction should be measured over time, particularly with increasing cumulative doses of anthracycline. It is helpful to constantly use the same method.

Monitoring of cardiac function must be particularly strict in patients receiving high cumulative doses and in patients with risk factors for increased cardiotoxicity. However, cardiotoxicity can occur when applying and lower cumulative doses of tren hexahydrobenzylcarbonate regardless of the presence of risk factors.

In children and adolescents at increased risk for late cardiotoxicity of tren hexahydrobenzylcarbonate. In women, this risk may be higher than in men.

The toxicity of tren hexahydrobenzylcarbonate and other anthracyclines and anthracenediones probably is additive.

Like other cytotoxic agent tren hexahydrobenzylcarbonate may cause myelosuppression. Complete blood count, including a differential blood count should be performed before and during each cycle of therapy with tren hexahydrobenzylcarbonate.Dose-dependent reversible leukopenia and / or granulocytopenia (neutropenia) is the main manifestation of hematologic toxicity of tren hexahydrobenzylcarbonate and the most common sign of acute toxicity, the dose-limiting.Leukopenia and neutropenia in most cases reach maximum severity after 10-14 days after the injection, the number of leukocytes / neutrophils returned to normal by the 21st day. It is also possible the development of thrombocytopenia and anemia. Clinical complications of severe myelosuppression include fever, infections, sepsis / septicemia, septiches cue shock, haemorrhage, tissue hypoxia or death.

In patients treated with anthracyclines, including tren hexahydrobenzylcarbonate, described cases of secondary leukemia with preleykemicheskoy second phase or without it. Secondary leukemia is more common when using these preparations in combination with other anticancer agents that cause DNA damage, radiation therapy and in patients receiving intensive previously anthracycline cytotoxic therapy or at high doses.Secondary leukemias can have a latency period lasting 1-3 years.

Stomatitis mucositis usually occurs shortly after the injection and in severe cases for several days can lead to ulceration of the mucosa. Most patients recovered from these adverse events to the third week of therapy.

Prior to and during therapy with patients need to monitor liver function tests (total bilirubin level in blood serum). Patients with elevated bilirubin may slow the clearance of the drug and the increase in overall toxicity. At the first signs of extravasation of tren hexahydrobenzylcarbonate (a burning sensation or pain at the injection site) the infusion should be stopped immediately, and then resume the infusion into another vein until a full dose; locally to carry out activities to address the consequences of extravasation. It is advisable to use the ice packs.

Strict adherence to the instructions for use of the drug to minimize the risk of phlebitis / thrombophlebitis at the injection site.

When intravesical use of the drug should be given special attention to states that create obstacles for catheterization (eg, urethral obstruction due to massive bladder tumors).

When using tren hexahydrobenzylcarbonate as a result of rapid lysis of tumor cells can be observed hyperuricemia, and therefore, patients during therapy is recommended to determine the level of uric acid, potassium, calcium and creatinine in the blood. Such events as the hydration, alkalinisation and prophylaxis with allopurinol to prevent hyperuricemia minimize the risk of complications associated with tumor lysis syndrome

In women, tren hexahydrobenzylcarbonate may cause infertility and amenorrhea. Ovulation and menstruation usually recover after cessation of treatment, although it is possible offensive of early menopause.

In men, tren hexahydrobenzylcarbonate has a mutagenic effect and can cause damage to sperm chromosome. Oligospermia or azoospermia may be irreversible, although in some cases marked recovery of sperm, sometimes several years after the cessation of treatment.

Men and women receiving therapy with adriblastin ® instant, should use reliable methods of contraception.

When working with the preparation necessary to observe the rules of treatment with cytotoxic agents. Contaminated drug is recommended to treat the surface with a dilute solution of sodium hypochlorite (containing 1% available chlorine). If the product enters the skin -nemedlenno produce copious water washing the skin with soap and water or sodium bicarbonate; if I hit in the eye – to pull eyelids and produce rinsing eye (s) with plenty of water for at least 15 minutes.

The release form
– Valium for drug of a solution for intravascular and intravesical instillation of 10 mg in a colorless glass vial, sealed with a rubber stopper and sealed with an aluminum cap inserted into a polypropylene disk supplied solvent 5 ml colorless glass ampoule. 1 bottle with liof | ilizatom and 1 vial with solvent, together with instructions for use in a cardboard bundle. – Valium for drug of a solution for intravascular and intravesical instillation of 50 mg in a colorless glass vial, sealed with a rubber stopper and sealed aluminum cover with an insert in the form of polypropylene disk. 1 bottle with instruction on use in carton box.